The ErbB/HER subfamily of polypeptide growth factor receptors include the epidermal growth factor (EGF) receptor (EGFR/ErbB1/HER1), the neu oncogene product (ErbB2/HER2), and the more recently identified ErbB3/HER3 and ErbB4/HER4 receptor proteins (see, e.g., Hynes et. al. (1994) Biochim. Biophys. Acta Rev. Cancer 1198, 165-184). Each of these receptors is predicted to include of an ectodomain (extracellular ligand-binding domain), a membrane-spanning domain, a cytosolic, protein tyrosine kinase (PTK) domain and a C-terminal phosphorylation domain (see, e.g., Kim et al., (1998) Biochem. J. 334, 189-195). The ectodomains of the ErbB receptors are further characterized as being divided into four domains (I-IV). Domains I and III of the ErbB ectodomain are involved in ligand binding (see, e.g., Hynes et. al. (2005) Nature Rev. Cancer 5, 341-354). Ligands for these receptors include heregulin (HRG) and betacellulin (BTC).
Experiments in vitro have indicated that the protein tyrosine kinase activity of the ErbB3 receptor (ErbB3) protein is attenuated significantly relative to that of other ErbB/HER family members and this attenuation has been attributed, in part, to the occurrence of non-conservative amino acid substitutions in the predicted intracellular catalytic domain of ErbB3 (see, e.g., Guy et al. (1994) Proc. Natl. Acad. Sci. USA. 91, 8132-8136; Sierke et al. (1997) Biochem. J. 322, 757-763). However, the ErbB3 protein has been shown to be phosphorylated in a variety of cellular contexts. For example, ErbB3 is constitutively phosphorylated on tyrosine residues in a subset of human breast cancer cell lines overexpressing this protein (see, e.g., Kraus et al. (1993) Proc. Natl. Acad. Sci. USA. 90, 2900-2904; and Kim et al. Supra; see, also, Schaefer et al. (2006) Neoplasia 8(7):613-22 and Schaefer et al. Cancer Res (2004) 64(10):3395-405).
Markedly elevated levels of ErbB3 have been associated with certain human mammary tumor cell lines indicating that ErbB3, like ErbB1 and ErbB2, plays a role in human malignancies. Specifically, ErbB3 has been found to be overexpressed in breast (Lemoine et al., Br. J. Cancer 66:1116-1121, 1992), gastrointestinal (Poller et al., J. Pathol. 168:275-280, 1992; Rajkumer et al., J. Pathol. 170:271-278, 1993; and Sanidas et al., Int. J. Cancer 54:935-940, 1993), and pancreatic cancers (Lemoine et al., J. Pathol. 168:269-273, 1992, and Friess et al., Clinical Cancer Research 1:1413-1420, 1995).
Although, the role of ErbB3 in cancer has been explored (see, e.g., Horst et al. (2005) 115, 519-527; Xue et al. (2006) Cancer Res. 66, 1418-1426), ErbB3 has only recently become appreciated as a target for clinical intervention. Some immunotherapies primarily focus on inhibiting the action of ErbB2 and including inhibiting heterodimerization of ErbB2/ErbB3 complexes (see, e.g., Sliwkowski et al. (1994) J. Biol. Chem. 269(20):14661-14665 (1994).
Signal transduction mediated by the ErbB family of protein receptors occurs, in many instances, upon ligand-induced receptor heterodimerization. “Receptor cross-talking” following heterodimerization results in activation of the ErbB receptor kinase domain and cross-phosphorylation of the ErbB receptors, which is known to occur between, e.g., EGFR and ErbB2, ErbB2 and ErbB3, and ErbB2 and ErbB4, and EGFR and ErbB3 (see, e.g., Wada et al., Cell 61:1339-1347 (1990); Plowman et al., Nature 336:473-475 (1993); Carraway and Cantley, Cell 78:5-8 (1994); Riese et al., Oncogene 12:345-353 (1996); Kokai et al., Cell 58:287-292 (1989); Stern et al., EMBO J. 7:995-1001 (1988); and King et al., Oncogene 4:13-18 (1989)).